The causal relationship between gut microbiota and diabetic neuropathy: a bi-directional two-sample Mendelian randomization study.

Background: Many studies suggest a strong correlation between gut microbiota (GM) and diabetic neuropathy (DN). However, the precise causal relationship between GM and DN has yet to be fully elucidated. Hence, a bi-directional Mendelian randomization (MR) analysis was used to examine the association between GM and DN. Methods: Widely known genome-wide association study (GWAS) of GM was collected from the MiBio Gen project. Summary-level datasets for DN were taken from the FinnGen project. Inverse variance weighted approach was used for evaluating the causal relationship between GM and DN. Subsequently, pleiotropy and heterogeneity tests were performed to verify the reliability of the data. Furthermore, a bidirectional two-sample MR analysis was done to investigate the directionality of the causal relationships. Gene Ontology analysis was conducted to identify the associations that could indicate biological functions. Results: We identified potential causal associations between GM and DN (p< 0.05 in all three MR methods). Among them, we found increased levels of Christensenellaceae R-7 (Odds ratio, OR= 1.52; 95% confidence interval, CI = 1.03-2.23; p = 0.03), Ruminococcaceae UCG013 (OR =1.35; 95% CI = 1.00-1.85; p = 0.04), and Eggerthella groups (OR = 1.27; 95% CI = 1.05-1.55; p = 0.01), which may be associated with a higher risk of DN, while increased levels of Peptococcaceae (OR = 0.69; 95% CI = 0.54-0.90; p< 0.01) and Eubacterium coprostanoligenes groups (OR = 0.68; 95% CI = 0.49-0.93; p = 0.01) could be associated with a lower risk. Gene Ontology pathway analysis revealed enrichment of genes regulated by the associated single-nucleotide polymorphisms (SNPs) in the apical plasma membrane, glycosyltransferase activity, hexosyltransferase activity and membrane raft. Reverse MR analyses indicated that DN was associated with five microbial taxa in all three MR methods. Conclusion: The results of our study validate the possible causative relationship between GM and DN. This discovery gives new perspectives into the mechanism on how GM influences DN, and establishes a theoretical foundation for future investigations into targeted preventive measures.

The Glu727 Allele of Thyroid Stimulating Hormone Receptor Gene is Associated with Osteoporosis.

BACKGROUND: Published data indicate that thyroid stimulating hormone receptor (TSHR) activities are associated with osteoporosis in some patients. AIM: This study aimed to elucidate whether a given polymorphism of the TSHR gene is associated with osteoporosis. MATERIALS AND METHODS: One hundred and fifty subjects with osteoporosis were recruited in this study. The diagnosis of osteoporosis was performed with quantitative ultrasound system. The TSHR gene polymorphism was examined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The results showed a nucleotide substitution in the first position of codon 36 of the TSHR gene. The nucleotide substitution was from G to C, leading to a (36)D → (36)H change (D36H) in the predicted amino acid sequence of the receptor. The change did not show significance between healthy subjects and patients with osteoporosis (P > 0.05). On the other hand, we identified another single nucleotide polymorphism that is a C-to-G substitution at codon 727 (GAC to GAG); its frequency was significantly higher in patients with osteoporosis than that in healthy subjects. Using logistic regression analysis, significant correlation was revealed between the genotype D727E and the serum levels of TSH, or the quantitative ultrasound value of the calcaneal bone. CONCLUSIONS: The present study suggests that the genotype D727E of the TSHR, but not the genotype D36H, may be a genetic risk factor for osteoporosis.